Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK

HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzym...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-12, Vol.20 (24), p.7429-7434
Main Authors: Tanis, Steven P., Plewe, Michael B., Johnson, Ted W., Butler, Scott L., Dalvie, Deepak, DeLisle, Dorothy, Dress, Klaus R., Hu, Qiyue, Huang, Buwen, Kuehler, Jon E., Kuki, Atsuo, Liu, Wen, Peng, Qinghai, Smith, Graham L., Solowiej, Jim, Tran, Khanh T., Wang, Hai, Yang, Anle, Yin, Chunfeng, Yu, Xiaoming, Zhang, Junhu, Zhu, Huichun
Format: Article
Language:English
Subjects:
ADME
Administration, Oral
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral
Antiviral activity
Antiviral agents
Azaindole hydroxamates
Bioavailability
Biological and medical sciences
Data processing
Dogs
Enzymes
Genomes
Half-Life
Hepatocytes
Hepatocytes - drug effects
HIV integrase
HIV Integrase - chemistry
HIV Integrase - metabolism
HIV Integrase Inhibitors - chemistry
HIV Integrase Inhibitors - pharmacokinetics
HIV Integrase Inhibitors - toxicity
HIV-1 - enzymology
Human immunodeficiency virus 1
Humans
Hydroxamic acid
Hydroxamic Acids - chemistry
Hydroxamic Acids - pharmacokinetics
Hydroxamic Acids - toxicity
Indoles - chemistry
Integrase
LipE
Log D
Medical sciences
Oxidative metabolism
Pharmacokinetics
Pharmacology. Drug treatments
Physicochemical parameters
Physicochemical properties
Replication
Structure-Activity Relationship
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Summary:HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the β-position of the azaindole core thereby altering physical properties by lowering calculated log D values ( c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.10.022